The synthesis, characterization, and in vitro activity of a cyclohexane-1R,2R-diamine-based Pt(IV) derivative containing the histone deacetylase inhibitor rac-2-(2-propynyl)octanoato, namely, (OC-6-44)-acetatodichlorido (cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV), are reported together with those of its isomers containing enantiomerically enriched axial ligands. These Pt(IV) complexes showed comparable activity, of 2 orders of magnitude higher than reference drug oxaliplatin on three human (HCT 116, SW480, and HT-29) and one mouse (CT26) colon cancer cell lines. In vivo experiments were carried out on immunocompetent BALB/c mice bearing the same syngeneic tumor. The complex (OC-6-44)-acetatodichlorido(cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV) showed higher tumor mass Pt accumulation than oxaliplatin, due to its higher lipophilicity, with negligible nephro- and hepatotoxicities when administered intravenously. A remarkable tumor mass invasion by cytotoxic CD8(+) T lymphocytes, following the Pt(IV) treatment, indicated a strong induction of immunogenic cell death.

Pt(IV) Bifunctional Prodrug Containing 2-(2-Propynyl)octanoato Axial Ligand: Induction of Immunogenic Cell Death on Colon Cancer

Sabbatini, Maurizio;Zanellato, Ilaria;Ravera, Mauro;Gabano, Elisabetta;Perin, Elena;Rangone, Beatrice;Osella, Domenico
2019-01-01

Abstract

The synthesis, characterization, and in vitro activity of a cyclohexane-1R,2R-diamine-based Pt(IV) derivative containing the histone deacetylase inhibitor rac-2-(2-propynyl)octanoato, namely, (OC-6-44)-acetatodichlorido (cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV), are reported together with those of its isomers containing enantiomerically enriched axial ligands. These Pt(IV) complexes showed comparable activity, of 2 orders of magnitude higher than reference drug oxaliplatin on three human (HCT 116, SW480, and HT-29) and one mouse (CT26) colon cancer cell lines. In vivo experiments were carried out on immunocompetent BALB/c mice bearing the same syngeneic tumor. The complex (OC-6-44)-acetatodichlorido(cyclohexane-1R,2R-diamine)(rac-2-(2-propynyl)octanoato)platinum(IV) showed higher tumor mass Pt accumulation than oxaliplatin, due to its higher lipophilicity, with negligible nephro- and hepatotoxicities when administered intravenously. A remarkable tumor mass invasion by cytotoxic CD8(+) T lymphocytes, following the Pt(IV) treatment, indicated a strong induction of immunogenic cell death.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11579/103010
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 56
  • ???jsp.display-item.citation.isi??? 55
social impact